A02 - Garcia-Saez & Pasparakis

A02 – Cross-talk between dying and bystander cells in vitro and in vivo: an optogenetics approach

Ana J. Garcia-Saez

Institute for genetics, CECAD, University of Cologne
Contact: garcia-office(at)uni-koeln.de
For more information see: Garcia-Saez lab

Manolis Pasparakis

Institute for genetics, CECAD, University of Cologne
Contact: pasparakis(at)uni-koeln.de
For more information see: Pasparakis lab

Abstract

Currently available tools do not allow studying the cross-talk between dying and bystander cells in a spatially and temporally resolved manner. The project aims to develop optogenetically regulated systems allowing the precisely controlled induction of different forms of cell death at a single cell level and use them to study the cross-talk between dying and bystander cells in vitro and in vivo. By employing selective light-controlled activation of different death effectors, this project will study how the different types of cell death shape tissue responses and the underlying mechanisms.

Recent Publications

2025

Ros U, Martinez-Osorio V, Valiente PA, Abdelwahab Y, Gojkovic M, Shalaby R, Zanna S, Saggau J, Wachsmuth L, Nemade HN, Zoeller J, Lottermoser H, Chen YG, Ibrahim M, Kelepouras K, Vasilikos L, Bedoya P, Espiritu RA, Müller S, Altmannova V, Tieleman DP, Weir J, Langer J, Adam M, Walczak H, Wong WW, Liccardi G, Mollenhauer M, Pasparakis M, Peltzer N, García-Sáez AJ. MLKL activity requires a splicing-regulated, druggable intramolecular interaction. Mol Cell. 2025 Apr 3:S1097-2765(25)00259-X. doi: 10.1016/j.molcel.2025.03.015. Epub vor dem Druck. PMID: 40209701

Roeck BF, Lotfipour Nasudivar S, Vorndran MRH, Schueller L, Yapici FI, Rübsam M, von Karstedt S, Niessen CM, Garcia-Saez AJ. Ferroptosis spreads to neighboring cells via plasma membrane contacts. Nat Commun. 2025 Mar 26;16(1):2951. doi: 10.1038/s41467-025-58175-w. PMID: 40140422; PMCID: PMC11947162.

Etxebeste-Mitxeltorena M, Flores-Romero H, Ramos-Inza S, Masiá E, Nenchova M, Montesinos J, Martinez-Gonzalez L, Porras G, Orzáez M, Vicent MJ, Gil C, Area-Gomez E, Garcia-Saez AJ, Martinez A. Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model. J Med Chem. 2025 Jan 8. doi: 10.1021/acs.jmedchem.4c01368. Epub ahead of print. PMID: 39778888.

Project A02 Publications 1st Funding Period 2020 - 2023

2023

Czabotar, P.E. and Garcia-Saez, A.J. (2023) Mechanisms of BCL-2 family proteins in mitochondrial apoptosis. Nat Rev Mol Cell Biol. doi: 10.1038/s41580-023-00629-4

Rieger, J., Fitz, M., Fischer, S.M., Wallmeroth, N., Flores-Romero, H., Fischer, N.M., Brand, L.H., García-Sáez, A.J., Berendzen, K.W. and Mira-Rodado, V. (2023) Exploring the Binding Affinity of the ARR2 GARP DNA Binding Domain via Comparative Methods. Genes (Basel). doi: 10.3390/genes14081638

Röck, B.F., Shalaby, R. and García-Sáez, A.J. (2023) Pyroptosis Induction and Visualization at the Single-Cell Level Using Optogenetics. Methods Mol Biol. 2696, 135-147. doi: 10.1007/978-1-0716-3350-2_10 (review)

Pedrera, L., Ros, U. and García-Sáez, A.J. (2023) Calcium as a master regulator of ferroptosis and other types of regulated necrosis. Cell Calcuim 114, 102778 . doi: https://doi.org/10.1016/j.ceca.2023.102778

Shalaby, R., Diwan, A., Flores-Romero, H., Hertlein, V., and Garcia Saez, A.J. (2023). Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation. Cell Death Differ 30, 731–741 https://doi.org/10.1038/s41418-022-01078-w

2022

Cosentino, K., Hertlein, V., Jenner, A., Dellmann, T., Gojkovic, M., Peña-Blanco, A., Dadsena, S., Wajngarten, N., Danial, J.S.H., Thevathasan, J.V., Mund, M., Ries, J., Garcia-Saez, A.J. (2022) The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation. Molecular Cell 82, 1-17, February 17, 2022 https://doi.org/10.1016/j.molcel.2022.01.008

2021

2020

Pedrera, L., Espiritu, R., A., Ros, U., Weber, J., Schmitt, A., Stroh, J., Hailfinger, S., von Karstedt, S., García-Sáez, A., J. (2020) Ferroptotic pores induce Ca 2+ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ Dec 17. doi: 10.1038/s41418-020-00691-x

Flores‐Romero, H., Ros, U., Garcia-Saez, A.J. (2020) Pore formation in regulated cell death. EMBO J (2020)e105753 https://doi.org/10.15252/embj.2020105753

Project related Publications

2011 - 2019

Ros, U., Pena-Blanco, A., Hanggi, K., Kunzendorf, U., Krautwald, S., Wong, W.W., and Garcia-Saez, A.J. (2017). Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium. Cell Rep 19, 175-187.

Cosentino, K., and Garcia-Saez, A.J. (2017). Bax and Bak Pores: Are We Closing the Circle? Trends Cell Biol 27, 266-275.

Bleicken, S., Hantusch, A., Das, K.K., Frickey, T., and Garcia-Saez, A.J. (2017). Quantitative interactome of a membrane Bcl-2 network identifies a hierarchy of complexes for apoptosis regulation. Nat Commun 8, 73.

Salvador-Gallego, R., Mund, M., Cosentino, K., Schneider, J., Unsay, J., Schraermeyer, U., Engelhardt, J., Ries, J., and Garcia-Saez, A.J. (2016). Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores. EMBO J 35, 389-401.

Bleicken, S., Hofhaus, G., Ugarte-Uribe, B., Schroder, R., and Garcia-Saez, A.J. (2016). cBid, Bax and Bcl-xL exhibit opposite membrane remodeling activities. Cell Death Dis 7, e2121.

Subburaj, Y., Cosentino, K., Axmann, M., Pedrueza-Villalmanzo, E., Hermann, E., Bleicken, S., Spatz, J., and Garcia-Saez, A.J. (2015). Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species. Nat Commun 6, 8042.

Bleicken, S., Jeschke, G., Stegmueller, C., Salvador-Gallego, R., Garcia-Saez, A.J., and Bordignon, E. (2014). Structural model of active Bax at the membrane. Mol Cell 56, 496-505.

Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, T., Hermance, N., Zelic, M., Kirsch, P., Basic, M., Bleich, A., Kelliher, M., and Pasparakis, M. (2014). RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90-94.

Bonnet, M.C., Preukschat, D., Welz, P.S., van Loo, G., Ermolaeva, M.A., Bloch, W., Haase, I., and Pasparakis, M. (2011). The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35, 572-582.

Welz, P.S., Wullaert, A., Vlantis, K., Kondylis, V., Fernandez-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., and Pasparakis, M. (2011). FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330-334.

UNIVERSITÄT ZU KÖLN

Sonderforschungsbereich 1403